FORMULATION AND EVALUATION OF ORAL DISPERSIBLE

TABLET OF TRAMADOL HYDROCHLORIDE

Dissertation Submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfillment for the award of the degree of

MASTER OF PHARMACYIn

PHARMACEUTICS

By

Reg. No: 26101005

Under the Guidance of

DR. R.Kumaravelrajan M. Pharm., Ph.D

Department of PharmaceuticsC.L.Baid Metha College of Pharmacy(An ISO 9001-2000 certified institute)

Thoraipakkam, Chennai – 600 097

April - 2012

THE CERTIFICATE

This is to certify that Reg. No: 26101005 carried out the dissertation work on

“FORMULATION AND EVALUATION OF ORAL DISPERSIBLE TABLET

OF TRAMADOL HYDROCHLORIDE” for the award of degree of MASTER

OF PHARMACY IN PHARMACEUTICS of THE TAMILNADU

DR. M. G. R. MEDICAL UNIVERSITY, CHENNAI and is bonafide record work

done by her under my Supervision and Guidance in the Department of

Pharmaceutics, C. L. Baid Metha college of Pharmacy, Chennai-600 097 during the

academic year 2011-2012.

Chennai – 97.

THE CERTIFICATE

This is to certify that Reg. No: 26101005 carried out the dissertation work on

“FORMULATION AND EVALUATION OF ORAL DISPERSIBLE TABLET

OF TRAMADOL HYDROCHLORIDE” for the award of degree of MASTER

OF PHARMACY IN PHARMACEUTICS of THE TAMILNADU DR. M. G. R.

MEDICAL UNIVERSITY, CHENNAI under the guidance and supervision of

DR. R.KUMARAVELRAJAN M. Pharm., Ph.D in the Department of

Pharmaceutics, C. L. Baid Mehta college of Pharmacy, Chennai-600 097 during the

academic year 2011-2012.

Chennai – 97. Dr. GRACE RATHNAM, M. Pharm., Ph.D

Principal and Head of the Department

Department of Pharmaceutics

C. L. Baid Metha college of Pharmacy

Chennai – 600 097.

DECLARATION

I do hereby declare that the thesis entitled “FORMULATION AND

EVALUATION OF ORAL DISPERSIBLE TABLET OF TRAMADOL

HYDROCHLORIDE” by Reg. No: 26101005 submitted in partial fulfillment for

degree of Master of Pharmacy in Pharmaceutics was carried out at C.L.Baid

Metha college of Pharmacy, Chennai-97 under the guidance and supervision of DR.

R.KUMARAVELRAJAN M. Pharm., Ph.D., and industrial guide Mr.Ramesh

Jagadeeshan, M.Pharm., during the academic year 2011-2012. The work

embodied in this thesis is original, and is not submitted in part or full for any other

degree of this or any other University.

Chennai – 97. Reg. No: 26101005

Department of Pharmaceutics

C. L. Baid Metha college of Pharmacy

Chennai – 600 097.

ABBREVIATIONS

FTIR Fourier transformer infrared spectroscopy

HCL Hydrochloric Acid

HPLC High performance liquid chromatography

HPMC Hydroxy propyl methyl cellulose

HP CD Hydroxypropyl cyclodextrin

IR Infrared spectroscopy

MCC Micro crystalline cellulose

MDT Mouth Dissolving Tablets

ODT Oral Dispersible Tablets

PVP Polyvinylpyrrolidine

SSG Sodium starch glycolate

UV Ultraviolet

XG Xanthan gum

NOMENCLATURE

% Percentage

µg/ml Microgram/millilitre

Conc Concentration

gm/cc Gram/cubic centimetre

Hr Hour

Kg/cm2 Kilogram/square centimetre

Min Minute

Mm Millimetre

Ng Nanogram

ng/ml Nanogram/millilitre

ng-hr/ml Nanogram-hour/millilitre

Nm Nanometer

SD Standard Deviation

Sec Seconds

CONTENTS

Chapter

NoTITLE Page No.

1 Introduction 1

2 Literature Review 19

3 Aim and Objective 29

4 Drug and Excipient Profile 30

5 Plan of Work 44

6 Materials and Methods 45

7 Results and Discussion 62

8 Summary and Conclusion 97

9 Bibliography 100

ACKNOWLEDGEMENT

It is a great time for me to acknowledge those without whom, this work

would not have been fruitful.

It gives me an immense pleasure in expressing my deep sense of gratitude to

my respected guide DR. R. Kumarvelrajan M.Pharm.,Ph.D., C.L.Baid Metha

college of pharmacy for his remarkable guidance, constant encouragement and every

scientific and personal concern through out the course of investigation and

successful completion of this work.

I would like to express my immense gratitude to my industrial guide

Mr.Ramesh Jagadeeshan, M.Pharm, Sr. Manager, Kemwell Biopharma,

Banglore for providing the great opportunity to carry out the project in Kemwell

Biopharma,for his valuable guidance and support in each and every aspect of the

project.

It is great pleasure and honor for me to owe gratitude to DR. Gracerathnam

M.Pharm, Ph.D. principal for all his support and for giving a valuable guidance and

scientific support to carry out this work.

I would like to thank Kemwell Biopharma, for giving me an opportunity to

perform my project work in their organization which helped me to mould my project

work into a successful one.

I owe my special thanks to Mr.Anil M.Pharm and Ms. Aaradhana for

their valuable Advices and cooperation in bringing out this project work.

I feel proud to express my hearty gratitude and appreciation to all my

Teaching and Non-teaching Staff members of C.L.Baid Metha College of

Pharmacy who encouraged to complete this work.

I feel proud to express my hearty gratitude to all my classmates. Also I want

to thank all of those, whom I may not be able to name individually, for helping me

directly or indirectly.

Last but not the least I wish to express my deepest sense to respect and love

to my parents for their constant support and encouragement throughout.

(Reg.No: 26101005)

1

An ideal dosage regimen in the drug therapy of any disease is the one,

which immediately attains the desire therapeutics concentration of drug in plasma

(or at the site of action) and maintains it constant for the entire duration of

treatment1.

Drugs are frequently taken by oral administration. Although a few drugs

taken orally are intended to be dissolved within the mouth, majority of drugs taken

orally are swallowed. Compared with alternate routes, the oral route of drug

administration is the most popular and has been successfully used for conventional

delivery of drug. It is considered as most natural, convenient means of administering

drugs2.

One important drawback of these dosage forms was many patients have

difficulty in swallowing tablets and hard gelatin capsules and consequently do not

take medications as prescribed. It is estimated that 50% of the population is affected

by this problem, which results in a high incidence of noncompliance and ineffective

therapy3. It has been reported that dysphagia (difficulty in swallowing) is common

among all age groups and more specific with pediatric, geriatric population along

with institutionalized patients and patients with nausea4.

This problem can be resolved by the creation of rapidly dispersing or

dissolving oral forms, which do not require water to aid swallowing. The dosage

forms are placed in the mouth, allowed to disperse or dissolve in the saliva, and then

are swallowed in the normal way3.

1.1 Oral Dispersible Tablet

This is an innovative tablet technology where the dosage form containing

active pharmaceutical ingredients disintegrates rapidly, usually in a matter of

seconds, without the need for water, providing optimal convenience to the patient.

Innovators and inventor companies have given these tablets various names such as

Orally disintegrating tablets (ODT), Mouth dissolving (MD), Fast melting, Fast

2

dissolving, Fast dispersing, Rapid dissolve,Rapid melt, Quick disintegrating,

Rapimelts, Melt-in-mouth tablets, Porous tablets or Orodisperse 5, 6.

British Pharmacopoeia defines oral dispersible tablets as uncoated tablets

intended to be placed in the mouth were they disperse rapidly before being

swallowed7.

1.2 Criteria for developing Oral Dispersible Tablets 5, 8, 9

Tablets should

Not require water to swallow, and should disintegrate or dissolve in

mouth in matter of seconds.

Have an acceptable taste masking.

Leave minimal or no residue in mouth after administration.

Have a pleasant mouth feel.

Be less sensitive to environmental conditions such as temperature and

humidity.

1.3 Salient features of Oral Dispersible Tablets 5, 9

Do not require water to swallow, which is convenient during

travelling and who do not have immediate access to water.

Ease of administration to the patients who are unable to swallow,

such as bedridden patients, stroke victims and patients who refuse to

swallow such as geriatric, pediatric & psychiatric patients.

Some drugs may be absorbed from the mouth, pharynx and

esophagus as the saliva passes down into stomach in those cases

bioavailability of the drug is increased.

The risk of suffocation during oral administration of conventional

tablet due to physical obstruction is avoided.

3

Good mouth feel property helps to change the perception of

medication as bitter pill.

1.4 Benefits of Oral Dispersible Tablets 5, 10

Administered without water anywhere and anytime.

Suitability for geriatric, pediatric, and bedridden or developmentally

disabled patients, patients with persistent nausea.

Beneficial in cases such as motion sickness, sudden episodes of

allergic attack or coughing, where an ultra rapid onset of action

required.

An increased bioavailability, particularly in cases of insoluble and

hydrophobic drugs, due to rapid disintegration and dissolution of

these tablets.

Stability for longer duration of time, since the drug remains in solid

dosage form till it is consumed. So, it combines advantage of solid

dosage form in terms of stability and liquid dosage form in terms of

bioavailability.

1.5 Limitations of Oral Dispersible Tablets 5, 8, 9, 10

o The tablets usually have low mechanical strength, so they are friable

or brittle and difficult to handle. So they require specialized peel-off

blister packing and careful handling.

o The tablets may leave unpleasant taste and/or grittiness in mouth if

not formulated properly.

o Drugs with relatively large doses are difficult to formulate into oral

dispersible tablets.

4

o Patients with Sjogren’s syndrome or dryness of mouth due to

decreased saliva production may not be good candidates for this

formulation.

o Patients who concurrently take anti cholinergic medication are not

suitable for oral dispersible tablets.

1.6 Challenges of Oral Dispersible Tablets 9, 10, 11

1.6.1 Fast Disintegration

ODTs should disintegrate in the mouth without the aid of water or with a

very small amount of water. The “fast disintegration” usually means disintegration

of tablets in less than 1 minute, but it is preferred to have disintegration as soon as

possible. The disintegration fluid is provided by the saliva of the patient.

1.6.2 Palatability

Oral dispersible tablets dissolve or disintegrate near the taste buds.

A pleasant taste inside the mouth becomes critical for patient acceptance. Unless the

drug is tasteless or does not have an undesirable taste, taste-masking techniques

should be used. An ideal taste-masking technique should provide good mouth feel

and should be compatible with ODT formulations. The amount of taste masking

material should be as low as possible to reduce the tablet size.

1.6.3 Tablet Strength and Porosity

In order to disintegrate the oral dispersible tablet in the oral cavity, the

tablet structure should have a highly porous network and should use low

compression force, which makes the tablets friable or brittle, which is difficult to

handle. Because the strength of a tablet is related to compression pressure, it is

important to find the porosity that allows fast water absorption while maintaining

high mechanical strength.

5

1.6.4 Hygroscopicity

Generally oral dispersible tablets are hygroscopic and cannot maintain

physical integrity under normal conditions of temperature and humidity. This

problem can be especially challenging because many highly water soluble excipients

are used in the formulation to enhance fast dissolving properties as well as to create

good mouth feel. Those highly water soluble excipients are susceptible to moisture.

Hence they need protection from various environmental conditions.

1.6.5 Size of Tablet

The degree of ease when taking a tablet depends on its size. It has been

reported that the easiest size of tablet to swallow is 7-8mm while the easiest size to

handle was one larger than 8mm. Therefore, the tablet size that is easy to take and

easy to handle is difficult to achieve.

1.6.6 Amount of Drug

ODTs are limited by the amount of drug that can be incorporated into each

unit dose. For lyophilized dosage forms, the drug dose must be lower than 400mg

for insoluble drugs and less than 60mg for soluble drugs. This parameter is

particularly challenging when formulating a fast-dissolving oral films.

1.7 Techniques Used For the Formulation of Oral Dispersible Tablets

Many techniques have been reported

1.7.1 Freeze-Drying or Lyophilization 12, 13, 14:

Freeze drying is the process in which water is sublimed from the product

after it is frozen. This technique creates an amorphous porous structure that can

dissolve rapidly. The active drug is dissolved or dispersed in an aqueous solution of

a carrier/polymer and the mixture is dosed by weight and poured in the wells of the

bluster packs. The trays holding the blister packs are passed through liquid nitrogen

6

freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister

packs are placed in refrigerated cabinets to continue the freeze-drying. After freeze-

drying the aluminum foil backing is applied on a blister-sealing machine. Finally the

blisters are packaged and shipped. The freeze-drying technique has improved

absorption and increase in bioavailability.

Disadvantages:

* Expensive and time consuming

* Fragility makes conventional packaging unsuitable for these products

and poor stability under stressed conditions.

1.7.2 Tablet Molding 15, 16

Molding process is of two types

Solvent method: Solvent method involves moistening the powder

blend with a hydro alcoholic solvent followed by compression at low

pressures in molded plates to form a wetted mass (compression

molding). The solvent is than removed by air-drying. The tablets

manufactured in this manner are less compact than the compressed

tablets and posses a porous structure that hastens dissolution.

Heat method: Heat molding process involves preparation of a

suspension that contains a drug, agar and sugar (e.g. mannitol or

lactose) and pouring the suspension in the blister packaging wells,

solidifying the agar at the room temperature to form a jelly and

drying at 30 C under vacuum.

The mechanical strength of molded tablets is a matter of great concern.

Binding agents, which increase the mechanical strength of the tablets, need to be

incorporated. Taste masking is an added problem to this technology. The taste

masked drug particles were prepared by spray congealing, a molten mixture of

7

hydrogenated cottonseed oil, sodium carbonate, lecithin, polyethylene glycol, and an

active ingredient, into a lactose based tablet triturate form. Compared to the

lyophillization technique, tablets produced by the molding technique are easier to

scale up for industrial manufacture.

1.7.3 Spray Drying 17, 18

In this technique, gelatin can be used as a supporting agent and as a matrix,

mannitol as a bulking agent and sodium starch glycolate or croscarmellose or

crospovidone are used as superdisintegrants. Tablets manufactured from the spray-

dried powder have been reported to disintegrate in less than 20 seconds in aqueous

medium. The formulation contained bulking agent like mannitol and lactose, a

superdisintegrant like sodium starch glycolate & croscarmellose sodium and acidic

ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate). This

spray-dried powder, which compressed into tablets showed rapid disintegration and

enhanced dissolution.

1.7.4 Sublimation 19, 20, 21

To generate a porous matrix, volatile ingredients are incorporated in the

formulation that is later subjected to a process of sublimation. Highly volatile

ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid,

camphor, naphthalene, urea, urethane and phthalic anhydride may be compressed

along with other excipients into a tablet. This volatile material is then removed by

sublimation leaving behind a highly porous matrix. Tablets manufactured by this

technique have reported to usually disintegrate in 10-20 sec. Even solvents like

cyclohexane, benzene can be used as pore forming agents.

8

Drug + Volatizing agent + Other excipients

Compression

Volatizing agent

Compressed tablet

Sublimation

° ° ° Pores developed on sublimation

Of volatilizing agent

Fig 1: Steps involved in Sublimation

1.7.5 Direct Compression 22, 23

Direct compression represents the simplest and most cost effective tablet

manufacturing technique. This technique can now be applied for the preparation of

ODT because of the availability of improved excipients especially

superdisintegrants and sugar based excipients.

1.7.5.1 Superdisintegrants

In many orally disintegrating tablet technologies based on direct

compression, the addition of superdisintegrants principally affects the rate of

disintegration and hence the dissolution. The presence of other formulation

ingredients such as water-soluble excipients and effervescent agents further hastens

the process of disintegration.

9

1.7.5.2 Sugar Based Excipients

This is another approach to manufacture ODT by direct compression. The

use of sugar based excipients especially bulking agents like dextrose, fructose,

isomalt, lactilol, maltilol, maltose, mannitol, sorbitol, starch hydrolysate,

polydextrose and xylitol, which display high aqueous solubility and sweetness, and

hence impart taste masking property and a pleasing mouthfeel. Mizumito et al have

classified sugar-based excipients into two types on the basis of molding and

dissolution rate.

Type 1 saccharides (lactose and mannitol) exhibit low mouldability but

high dissolution rate.

Type 2 saccharides (maltose and maltilol) exhibit high mouldability and

low dissolution rate.

1.7.6 Cotton Candy Process24

The cotton candy process is also known as the “candy floss” process and

forms on the basis of the technologies such as Flash Dose30 (Fuisz Technology). An

ODT is formed using a candyfloss or shear form matrix; the matrix is formed from

saccharides or polysaccharides processed into amorphous floss by a simultaneous

action of flash melting and centrifugal force. The matrix is then cured or partially

recrystallised to provide a compound with good flow properties and compressibility.

The candyfloss can then be milled and blended with active ingredients and other

excipients and subsequently compressed into ODT. However, the high processing

temperature limits the use of this technology to thermostable compounds only.

1.7.7 Mass-Extrusion 25, 26

This technology involves softening the active blend using the solvent

mixture of water-soluble polyethylene glycol and methanol and subsequent

expulsion of softened mass through the extruder or syringe to get a cylinder of the

10

product into even segments using heated blade to form tablet. The dried cylinder can

also be used to coat granules for bitter drugs and thereby achieve taste masking.

1.8 Patented Technologies for Mouth Dissolving Tablets 27-31

Zydis Technology.

Durasolve Technology.

Orasolve Technology.

Flash Dose Technology.

Wow Tab Technology.

Flash Tab Technology.

Oraquick Technology.

Quick –Dis Technology.

Nanocrystal Technology.

1.8.1 Zydis Technology

Zydis, the best known of the mouth-dissolving/disintegrating tablet

preparations, was the first marketed new technology tablet. A Zydis tablet is

produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of

gelatin. The product is very lightweight and fragile, and must be dispensed in a

special blister pack. The Zydis product is made to dissolve on the tongue in 2 to 3

seconds. A major claim of the Zydis product is increased bioavailability compared

to traditional tablets. Because of its dispersion and dissolution in saliva while still in

the oral cavity, there can be a substantial amount of pre-gastric absorption from this

formulation. Any pre-gastric absorption avoids first-pass metabolism and can be an

advantage in drugs that undergo a great deal of hepatic metabolism. There are some

disadvantages to the Zydis technology. As mentioned earlier, the Zydis formulation

is very lightweight and fragile, and therefore should not be stored in backpacks or

the bottom of purses. Finally, the Zydis formulation has poor stability at higher

11

temperatures and humidities. It readily absorbs water, and is very sensitive to

degradation at humidities greater than 65%. Example: loratidine

1.8.2 Orasolve Technology

OraSolve was Cima's first mouth-dissolving/disintegrating dosage form.

The OraSolve technology, unlike Zydis, disperses in the saliva with the aid of

almost imperceptible effervescence. The OraSolve technology is best described as a

mouth disintegrating tablet; the tablet matrix dissolves in less than one minute,

leaving coated drug powder. The major disadvantage of the OraSolve formulations

is its mechanical strength. The OraSolve tablet has the appearance of a traditional

compressed tablet. However, the OraSolve tablets are only lightly compressed,

yielding a weaker and more brittle tablet in comparison with conventional tablets.

An advantage that goes along with the low degree of compaction of OraSolve is that

the particle coating used for taste masking is not compromised by fracture during

processing. These formulations can accommodate single or multiple active

ingredients and tablets containing more that 1.0 g of drug have been developed.

Their disintegration time is less than 30 seconds. The OraSolve formulations are not

very hygroscopic. Example: zolmitriptan

1.8.3 Durasolve Technology

DuraSolve is Cima's second-generation mouth-dissolving/disintegrating

tablet formulation. Produced in a fashion similar to OraSolve, DuraSolve has much

higher mechanical strength than its predecessor due to the use of higher compaction

pressures during tableting. DuraSolve tablets are prepared by using conventional

tabletting equipment and have good rigidity (friability less than that 2%). The

DuraSolve product is thus produced in a mouther and more cost-effective manner.

DuraSolve is so durable that it can be packaged in traditional blister packaging,

pouches or vials. One disadvantage of DuraSolve is that the technology is not

compatible with larger doses of active ingredients, because the formulation is

subjected to such high pressures on compaction. Example: risperidone

12

1.8.4 Flash Dose Technology

The Flash Dose technology utilizes a unique spinning mechanism to

produce a floss-like crystalline structure, much like cotton candy. This crystalline

sugar can then incorporate the active drug and be compressed into a tablet. This

procedure has been patented by Fuisz and is known as Shearform. The final product

has a very high surface area for dissolution. It disperses and dissolves quickly once

placed onto the tongue. Flash dose tablets consist of self–binding shearform matrix

termed as “floss”. Shearform matrices are prepared by flash heat processing and are

of two types. Example: ibuprofen

1.8.5 Wowtab Technology

The Wowtab mouth-dissolving/disintegrating tablet formulation has been

on the Japanese market for a number of years. The WOW in Wowtab signifies the

tablet is to be given “Without Water”. The Wowtab technology utilizes sugar and

sugar-like (e.g., mannitol) excipients. This process uses a combination of low

mouldability saccharides (rapid dissolution) and high mouldability saccharide (good

binding property).The two different types of saccharides are combined to obtain a

tablet formulation with adequate hardness and mouth dissolution rate. Due to its

significant hardness, the Wowtab formulation is a bit more stable to the environment

than the Zydis or OraSolve. It is suitable for both conventional bottle and blister

packaging. The Wowtab product dissolves quickly in 15 seconds or less. Example:

famotidine

1.8.6 Flashtab Technology

Prographarm laboratories have patented the Flashtab technology. This

technology involves the preparation of rapidly disintegrating tablet which consists of

an active ingredient in the form of microcystals. Drug microgranules may be

prepared by using the conventional techniques like coacervation, extrusion-

spheronization, simple pan coating methods and microencapsulation. The

microcrystals of microgranules of the active ingredient are added to the granulated

13

mixture of excipients prepared by wet or dry granulation, and compressed into

tablets. All the processing utilized the conventional tabletting technology, and the

tablets produced are reported to have good mechanical strength and disintegration

time less than one minute. Example: ibuprofen

1.8.7 Oraquick Technology

The Oraquick mouth-dissolving/disintegrating tablet formulation utilizes a

patented taste masking technology. The taste masking process does not utilize

solvents of any kind, and therefore leads to mouther and more efficient production.

Also, lower heat of production than alternative mouth-dissolving/disintegrating

technologies makes Oraquick appropriate for heat-sensitive drugs. KV

Pharmaceutical claims that the matrix that surrounds and protects the drug powder in

microencapsulated particles is more pliable, meaning tablets can be compressed to

achieve significant mechanical strength without disrupting taste masking. Oraquick

claims quick dissolution in a matter of seconds, with good taste-masking. There are

no products using the Oraquick technology currently on the market, but KV

Pharmaceutical has products in development such as analgesics, scheduled drugs,

cough and cold, psychotropics, and anti-infectives. Example: hyoscyamine sulfate

1.8.8 Quick –Dis Technology

Lavipharm has invented an ideal intra-oral mouth dissolving drug delivery

system, which satisfies the unmet needs of the market. The novel intra-oral drug

delivery system, trademarked Quick-Di, is Lavipharm’s proprietary patented

technology and is a thin, flexible, and quick-dissolving film. The film is placed on

the top or the floor of the tongue. It is retained at the site of application and rapidly

releases the active agent for local and/or systemic absorption. The typical

disintegration time is only 5 to 10 seconds for the Quick-Di film with a thickness of

2 mm. The dissolving time is around 30 seconds for Quick Di film with a thickness

of 2 mm.

14

1.8.9 Nanocrystal Technology

For mouth dissolving tablets, Elan's proprietary NanoCrystal technology

can enable formulation and improve compound activity and final product

characteristics. Decreasing particle size increases the surface area, which leads to an

increase in dissolution rate. This can be accomplished predictably and efficiently

using NanoCrystal technology. NanoCrystal particles are small particles of drug

substance, typically less than 1000 nm in diameter, which are produced by milling

the drug substance using a proprietary wet milling technique. NanoCrystal colloidal

dispersions of drug substance are combined with water-soluble ingredients, filled

into blisters, and lyophilized. The resultant wafers are remarkably robust, yet

dissolve in very small quantities of water in seconds. Example: rapamycin

1.9 Mechanism of Superdisintegrants 32, 33, 34

The tablet breaks to primary particles by one or more of the mechanisms

listed below

1.9.1 Wetting

When disintegrants with exothermic properties gets wetted, localized stress

is generated due to capillary air expansion, which helps in disintegration of tablet.

This explanation, however, is limited to only a few types of disintegrants and cannot

describe the action of most modern disintegrating agents.

1.9.2 Swelling

Perhaps the most widely accepted general mechanism of action for tablet

disintegration is swelling. Tablets with high porosity show poor disintegration due to

lack of adequate swelling force. On the other hand, sufficient swelling force is

exerted in the tablet with low porosity. It is worthwhile to note that if the packing

fraction is very high, fluid is unable to penetrate in the tablet and disintegration is

again slows down.

15

1.9.3 Porosity and capillary action (Wicking):

Disintegration by capillary action is always the first step. When we put the

tablet into suitable aqueous medium, the medium penetrates into the tablet and

replaces the air adsorbed on the particles, which weakens the intermolecular bond

and breaks the tablet into fine particles. Water uptake by tablet depends upon

hydrophilicity of the drug/excipient and on tableting conditions. For these types of

disintegrants maintenance of porous structure and low interfacial tension towards

aqueous fluid is necessary which helps in disintegration by creating a hydrophilic

network around the drug particles.

Wicking Swelling

Water is pulled into pores by Particles swell and break updisintegrant and reduced the physical the matrix form within; swellingbonding force between particles. Setup; localized stress spreads

throughout the matrix.

Fig. 2: Disintegration of Tablet by Wicking and Swelling

1.9.4 Particle Repulsive Theory

Another mechanism of disintegration attempts to explain the swelling of

tablet made with ‘non-swellable’ disintegrates. Guyot-Hermann has proposed a

particle repulsion theory based on the observation that non-swelling particle also

cause disintegration of tablets. The electric repulsive forces between particles are the

16

mechanism of disintegration and water is required for it. Researchers found that

repulsion is secondary to wicking.

1.9.5 Deformation

During tablet compression, disintegrated particles get deformed and these

deformed particles get into their normal structure when they come in contact with

aqueous media or water. Occasionally, the swelling capacity of starch was improved

when granules were extensively deformed during compression. This increase in size

of the deformed particles produces a breakup of the tablet. This may be a

mechanism of starch and has only recently begun to be studied.

Deformation Repulsion

Particles swell to pre compression Water is drawn into pores andsize and break up the matrix particles repel each otherbecause of the resulting electrical force

Fig 3: Disintegration of Tablet by Deformation and Repulsion

1.9.6 Release of Gases

Carbon dioxide released within tablets on wetting due to interaction

between bicarbonate and carbonate with citric acid or tartaric acid. The tablet

disintegrates due to generation of pressure within the tablet. This effervescent

mixture is used when pharmacist needs to formulate very rapidly dissolving tablets

or fast disintegrating tablet. As these disintegrants are highly sensitive to small

changes in humidity level and temperature, strict control of environment is required

17

during manufacturing of the tablets. The effervescent blend is either added

immediately prior to compression or can be added in to two separate fraction of

formulation.

Table 1 List of Superdisintegrants35

Superdisintegrants Example Mechanism ofaction

Special comment

Crosscarmellose®

Ac-Di-Sol®

Nymce ZSX®

Primellose®

Solutab®

Vivasol®

L-HPC

Crosslinkedcellulose

-Swells 4-8folds in < 10seconds.-Swelling andwicking both.

-Swells in twodimensions.-Direct compression orgranulation

-Starch free

CrosspovidoneCrosspovidon M®

Kollidon®

Polyplasdone®

CrosslinkedPVP

-Swells verylittle and returnsto original sizeaftercompression butact by capillaryaction

-Water insoluble andspongy in nature so getporous tablet

Sodium starchglycolateExplotab®

Primogel®

Crosslinkedstarch

-Swells 7-12folds in <30 seconds

-Swells in threedimensions and highlevel serve as sustainrelease matrix

Alginic acid NFSatialgine®

Crosslinkedalginic acid

-Rapid swellingin aqueousmedium orwicking action

-Promote disintegrationin both dry or wetgranulation

Soy polysaccharidesEmcosoy®

Natural superdisintegrant

-Does not contain anystarch or sugar. Used innutritional products.

Calcium silicate -Wickingaction

-Highly porous,-Light weight-Optimum concentrationis between 20-40%

18

Table 2 Commercially Available Mouth Dissolving Tablets36

Technologies Trade Name Active Ingredient Manufacturer

Feldene Fast Melt Piroxicam Pfizer, USA

Claritin Redi Tab Loratidine Schering plough, USA

Maxalt MLT Rizatriptan Merck, USA

Zyprexia Olanzepine Eli Lilly, USA

Pepcid RPD Famotidine Merck, USA

Zofran ODT Ondansetron Glaxo, UK

Zooming ZMT Zolmitriptan AstraZeneca, USA

Freeze Drying

Zelapar TM Selegilline Amarin,UK

Tempra Quicklets Acetaminophen Bristol Myers, USA

Febrectol Paracetamol Prographarma, France

Nimulid MDT Nimesulide Panacea Biotech, India

Torrox MT Rofecoxib Torrent pharma, India

Olanex Instab Olanzapine Ranbaxy, India

DisintegrantAddition

Romilast Montelukast Ranbaxy, India

Sugar BasedExcipient

Benadryl FastmeltDiphenhydramine& Pseudoephedrine

WarnerLambert, USA

19

Literature Review

Asija Rajesh et al., (2012)37 investigation was to mask the bitter taste

of tramadol hydrochloride and develop the orodispersible tablets and

study the effect of various factors on percent drug complexation. Ion

exchange resins like Kyron-114, Indion-234 and Tulsion-339 were

used in different ratios to mask the taste by forming the complex.

Superdisintegrants like Kyron-314 and crascarmellose sodium were

used in different concentrations and tablets were formulated by direct

compression.

Mansing G. Patil et al., (2011)38 in their article reviewed taste

masking, formulation and evaluation of Tramadol hydrochloride. In

the present study an attempt has been made to prepare bitter less

orally disintegrating tablet of Tramadol hydrochloride using Eudragit

E100 as a taste masking agent. Superdisintegrants like crospovidone,

croscarmellose sodium and sodium starch glycolate were used, the

prepared blend was evaluated for pre-compressional parameters.

Tablets were compressed by Mass extrusion technique and evaluated.

Thus the study concludes, successful taste masking and tablets

contain crospovidone showed fastest disintegration.

Ganure Ashok L et al., (2011)39 developed mouth dissolving tablets

of tramadol hydrochloride. The bitter taste of drug is prevented by

coating granules with isopropanol for specific duration after wet

granulation, the granules were then formulated with Aspartame,

MCC, Sodium croscarmellose and Sodium starch glycolate and

compressed by direct compression technique. Different types of

evaluation parameters for the tablets were used. Evaluation of the

tablets showed that all the tablets were found to be within official

limits.

20

Neeharika V et al.,(2011)40 designed to study the difference in

disintegration time, wetting efficiency of poorly soluble levofloxacin

and freely soluble tramadol hydrochloride using natural and synthetic

superdisintegrant. The effect of natural superdisintegrants like

isolated mucilage of Plant ago ovate, Hibiscus rosa-sinensis and

synthetic superdisintegrants like croscarmellose sodium (Ac-Di-Sol)

were compared in different concentrations. The blend were evaluated

for pre-compression parameters and formulated by direct

compression technique. The tablets were evaluated and the

physicochemical parameters of dried powdered mucilage were

studied. The results showed that natural super disintegrants found to

have better disintegration property than the synthetic super

disintegrant. The comparative study of poorly soluble levofloxacin

and freely soluble tramadol hydrochloride did not show any

difference in disintegration time or wetting efficiency with natural or

synthetic disintegrants.

Mahaveer Pr. Khinchi et al., (2011)41 developed the orally dispersible

tablets of Famotidine. Superdisintegrants like Ac-Di-Sol,

Crospovidone, Sodium starch glycolate and diluents like dibasic

calcium phosphate were used in the formulation of tablets. The

tablets were prepared by direct compression and were evaluated. In

this study maximum drug release and minimum disintegration time

were observed with crospovidone.

Parikh Bhavik AnjanKumar et al., (2011)42 designed and evaluated

taste mask oral disintegration tablet of lornoxicam. Taste making is

done by complexation with -cyclodextrin by Kneading method.

Crospovidone was used as superdisintegrant and tablets were

formulated by sublimation technique and effervescent method. The

prepared tablets were evaluated. The results showed that the tablets

prepared by sublimation technique have more % of drug release than

that by effervescent method.

21

Ganga Srinivasan et al., (2011)43 worked in formulation development

and evaluation of tramadol hydrochloride orally disintegrating tablets

using galen IQ as a diluents. Superdisintegrants like Crospovidone,

Croscarmellose sodium, Sodium starch glycolate and Starch 1500.

Tablets were prepared by direct compression technique and

evaluated. This study suggest that galen IQ could be successfully

used as a diluent in the formulation of tramadol hydrochloride orally

disintegrating tablet.

Nitesh J Patel et al., (2011)44 research was to compare the effect of

subliming agents on the oral dispersible property of cinnarizine

tablets. Compressed tablets prepared by using soluble material like

mannitol which has low porosity. Subliming agents like camphor,

menthol, ammonium bicarbonate or thymol were used in the

development of oral dispersible tablets by sublimation technique to

increase the porosity of the tablets. A high porosity was achieved.

Sagar Shanti et al., (2011)45 sustained release implant of tramadol

were prepared by extrusion method using specially designed extruder

with biodegradable naturally occurring polymer chitosan. By varying

the concentration of polymer and crosslinking time, these implants

could be used for pain management such as carcinomas, post

operative surgery, osteoarthritis, by suitable modification

Paul et al., (2011)46 studied the effects of disintegrants in different

concentration on the release profile of zidovudine ODTs. Differtent

superdisintegrants like crospovidone (PPXL), croscarmellose sodium

(Ac-Di-Sol), sodium starch glycolate were used in formulating the

tablets by direct compression method. Developed ODTs were studied

for their physicochemical properties. Ac-Di-Sol 6% possessed least

disintegration time and offered better dissolution profile

22

Prakash Goudanavar et al., (2011)47 develop the orodispersible tablet

of lamotrigine. Bitter taste of the drug is successfully masked by

forming inclusion complex with hydroxypropyl -cyclodextrin

employing Kneading method. The complex was compressed into

tablets along with superdisintegrants such as Kyron T-314, sodium

starch glycolate, Indion-414, croscarmellose sodium and

crospovidone in different concentration. HP CD is also useful to

enhance the solubility. Orodispersible tablets were characterized by

Fourier Transformer Infrared Spectroscopy, Differential Scanning

Calorimetry and Powder X-Ray Diffraction Analysis. The prepared

tablets were evaluated. Formulation containing higher concentration

of Indion-414 decreases disintegration time and optimize the drug

release.

Dayakar Rao Kalakuntla et al., (2011)48 develop a bitterless oral

disintegrating tablet of Lornoxicam. Lornoxiam is a non steroidal

anti-inflammatory drug belongs to the class oxicams. Taste masking

is done by complexing Lornoxicam with Eudragit E100.

Superdisintegrants like sodium starch glycolate and Indion-414. The

tablets were evaluated.

Sunitha S et al., (2011)49 determine the effect of solvents on

microencapsulation tramadol hydrochloride. Solvents like acetone,

dimethyldigol, 1,4-dioxan and non-solvents like n-hexane and

chloroform. The microspheres were prepared by following

coacervation phase separation using various non-aqueous solvents.

Microspheres were characterized for the particle size distribution,

wall thickness by scanning electron microscopy. The curve fitting

data revealed that the release followed first order kinetics.

Mishra S.K et al., (2011)50 develop once daily controlled release

matrix tablets of Tramadol Hcl. Using different polymers like

Eudragit RS-100, Ethylcellulose, Carbopol 934P and Polyvinyl

Pyrolidone controlled release matrix tablets of tramadol HCL were

23

formulated and evaluated. Different release models were applied to

in-vitro drug release data in order to evaluate the drug release

mechanisms and kinetics.

Shankar Avulapati et al., (2010)51 this study was to incorporate a

combination of superdisintegrants in optimum concentrations which

can minimize disintegration time of losartan potassium ODTs. The

various superdisintegrants used in the present study were sodium

starch glycolate, croscarmellose sodium, crospovidone. Tablets were

formulated by direct compression and evaluated for various

physicochemical parameters.

Kumar N et al., (2010)52 developed fast dissolving tablets of

granisetron hydrochloride. A combination of superdisintegrants like

sodium starch glycolate-crospovidone, sodium starch glycolate-

croscarmellose sodium and sodium starch glycolate-L-hydroxy

propyl cellulose were used along with mannitol to enhance mouth

feel. Tablets were prepared by direct compression technique and

evaluated. Among all formulations, the formulation using 4%w/w

sodium starch glycolate and 2%w/w of crospovidone was found to be

a promising formulation.

Suhas M. Kakade et al., (2010)53 development of orally disintegrating

tablets of sertraline to achieve a better dissolution rate. Orally

disintegrating tablets which dissolve or disintegrate instantly on the

patient tounge or buccal mucosa it is suited for tablets undergoing

high first pass metabolism and is used for improving bioavailability.

Sertraline is practically slightly soluble in water and extensively

absorbed after oral administration, the absolute bioavailability is

approximately 44% due to hepatic metabolisim. Superdisintegrants

like crospovidone, croscarmellose sodium and sodium starch

glycolate were used in formulating tablets by direct compression

technique. The tablets prepared were evaluated. Thus the study states

that crospovidone showed maximum dissolution rate.

24

Sunil H. Makwana et al., (2010)54 research was to mask the intensely

bitter taste of ondansetron Hcl and to formulate a orodispersible of

the taste masked drug. Taste masking was done using Indion-204 by

solvent evaporation technique in different ratios. Drug-resin complex

were optimized by considering parameters such as optimization of

resin concentration, swelling time, stirring time, pH and temperature

on maximum loading. Resinate was evaluated for taste masking,

characterized by X-Ray diffraction and infra red spectrometer. Thus,

results conclusively demonstrated successful masking of taste and

rapid disintegration of the formulated tablets in the oral cavity.

Suhas M. Kakade et al., (2010)55 design the mouth dissolving tablets

of losartan potassium with a view to enhance the patient compliance

and provide quick onset of action. Due to first pass metabolisim of

losartan potassium it has low solubility. Mouth dissolving tablets

prepared by direct compression and using superdisintegrants like

Polyplasdone XL 10, Croscarmellose sodium and Explotab in

different concentration and evaluated for the pre-compression

parameters. The prepared batches of tablets were evaluated. Among

all formulations Polyplasdone XL 10 was considered to be best

formulation.

B. K. Sridhar et al., (2010)56 develop and evaluate inclusion complex

of isoxsuprine hydrochloride. Taste masking was done by forming

inclusion complex with -cyclodextrin using Kneading method.

Tablets were prepared using superdisintegrants like sodium starch

glycolate, Ac-Di-Sol, crospovidone by direct compression. The

tablets were evaluated. The formulation having Ac-Di-Sol 5%

showed complete release of drug.

Vineet Bhardwaj et al., (2010)57 objective was to prepare the mouth

dissolving tablet of Amlodipine. Superdisintegrants such as Ac-Di-

Sol, sodium starch glycolate, Kollidon-CL using different

concentrations. Camphor was used as a sublimating agent. Tablets

25

were prepared by direct compression using mannitol as bulking

agent. The compressed tablets are dried for 5 hours to allow

sublimation of camphor to increase the porosity and tablets were

evaluated. Ac-Di-Sol showed least disintegrating time and fast

dissolution.

S. K. Sheth et al., (2010)58 develop a taste masked oral disintegrating

tablet of poorly soluble lornoxicam. Taste masking is done by

complexation with -cyclodextrin. Various superdisintegrants like

sodium starch glycolate, crospovidone, croscarmellose sodium were

used in formulating by direct compression method. Prepared tablets

were evaluated for various properties and stability studies were

conducted as per ICH guidelines. In this study tablets showed

enhanced dissolution.

Jaykar .B et al., (2010)59 develop orodispersible tablets of terbutaline

sulphate which is widely used as a bronchial asthma. Tablets were

compressed using ac-di-sol, sodium carboxy methyl cellulose, alginic

acid, chitosan and microcrystalline cellulose by direct compression

method. Prepared tablets were evaluated.

N.Kanakadurga devi et al., (2010)60 develop the formulation for

montelukast sodium which overcomes problems such as difficulty in

swallowing, inconvenience in administration. Attempt has been made

to prepare fast disintegrating tablets of montelukast sodium in the

oral cavity. Superdisintegrants like polyplasdone XL 10, Ac-Di-Sol

and primojel were used. The pure drug and formulation blend was

evaluated for pre-compressional parameters.tablets were prepared by

direct compression method and evaluated. Polyplasdone XL 10 was

recommended as asuitable disintegrant for the preparation of direct

compression melt-in-mouth tablets.

Metker Vishal et al., (2010)61 to develop mouth dissolving tablets of

lornoxicam. A novel superdisintegrant Kyron T-314(polacrillin

26

potassium) and menthol as subliming agent were used in the

formulation by wet granulation technique. The present study showed

rapid absorption, improved bioavailability, effective therapy and

patient compliance.

Vinayak S. Modi et al.,(2010)62 design and evaluate matrix controlled

release delivery system of a highly water-soluble analgesic, tramadol

hydrochloride using HPMC K 100 M and Xanthan Gum alone and in

combination as retarding polymers. Tablets were prepared by direct

compression and wet granulation using PVP K 30 as granulating

agent. HPMC and XG were used alone. Combinations were designed

by using 32 – full factorial design. The wet granulation and directly

compressed tablets showed good flow property and compressibility.

For a water soluble drug single polymer like HPMC K 100 M or

Xanthan gum could not retard the release for longer time. But the

combination of these polymers significantly retarded the release rate.

Raval S.B et al.,(2009)63 reported bitter less mouth dissolving tablets

of Tramadol hydrochloride using ion-exchange resin Indion-294 as

taste masking agent. Ion exchange resinates and tasteless granules

were prepared with Indion-294 in the ratio 1:2. The mouth dissolving

tablets of both resinates and granules were prepared with different

superdisintegrants like Croscarmellose sodium, Crospovidone and

Indion-234 in different concentration. The blend was examined for

their flow properties and tablets were evaluated for physiochemical

properties. The study concluded that tablets prepared by addition of

superdisintegrant Indion 234 have less disintegration time, fast and

more release than those prepared by crospovidone.

C.P.Jain et al., (2009)64 formulated and evaluated fast dissolving

tablets of valsartan. Sodium starch glycolate, crospovidone,

croscarmellose sodium are the superdisintegrants used. Tablets were

prepared by direct compression technique and evaluated for physico-

chemical properties. Effect of disintegrant on disintegration

27

behaviour of tablet in artificial saliva was evaluated. The release of

valsartan from fast dissolving tablets was found to follow non-

Fickian diffusion kinetics. Crospovidone showed fastest

disintegration.

Neena Bedi et al., (2009)65 develop the mouth dissolving tablets of

oxacarbazepine. In this study mouth dissolving tablets were prepared

using two different technologies, direct compression method and

solid dispersion technology. Tablets produced by direct compression

method contain cospovidone as a super disintegrant and aspartame as

a sweetener. Tablets produced by solid dispersion technique contain

polyvinylpyrrolidine K-30 and polyethylene glycol 6000 in different

ratios to increase its water solubility. The results compared for both

the technologies showed that the oxcarbazepine tablets prepared

using solid dispersion technology was found to have good

technological properties.

Parmar R.B. et al., (2009)66 develop a formulation which overcomes

problems such as difficulty in swallowing, inconvenience in

administration. The present research work was to held to develop fast

dissolving tablet of domperidone. Superdisintegrants like sodium

starch glycolate used in formulation by direct compression method.

All formulations were evaluated.

Amrit B. Karmarkar et al., (2008)67 research was to develop in situ

gelling, bioadhesive nasal inserts of tramadol hydrochloride by

lyophilisation of polymer gel solutions. The prepared nasal inserts are

a new dosage form having a sponge-like structure. The bioadhesion

potential was significantly dependent on the Carbopol 971P:

polycarbophil weigh ratio. Diffusion across the nasal mucosa shows a

matrix-type profile and the T50% was found to increase as the

concentration of polycarbophil increased.

.

28

Adamo Fini et al., (2008)68 developed ibuprofen orally disintegrating

tablets. To prevent the bitter taste, the drug was associated with

Phospholipon-80H, a saturated lecithin, by wet granulation. The

granules were then coated using different film forming agents like

Kollicoat SR 30, Kollidon-90F, Eudragit RD 100. Coated granules

were formulated with superdisintegrants like Kollidon CL or

Explotab and a mannitol- based diluents like Pearlitol SD 200.

Combined action of hydrophobic lecithin and the coating delay the

release of the drug from the tablets. It was thus possible to obtain

orally disintegrating tablets and a delayed release of ibuprofen.

B. Mishra et al., (2006)69 present study was to formulate and evaluate

matrix tablets of tramadol hydrochloride to achieve sustained drug

release with reduced frequency of drug administration, side effects

and improved patient compliance. Matrix tablets of tramadol HCL

were prepared by direct compression technique, using polymers like

HPMC, guar gum, xanthan gum alone and in combination in different

proportions. The drug release characteristics from matrix tablets were

compared with commercial sustained release tablet of tramadol

hydrochloride. Matrix tablets having HPMC prolonged the rate and

extent of drug release maximally followed by xanthan gum and gaur

gum. Increasing percentage of sodium carbonate in core further

prolonged the rate and extent of drug release.

29

Aim and Objective

The aim of the present investigation was to develop the formulation of

Tramadol hydrochloride orally dispersible tablet using direct compression

technique.

The objective of the study to clarify the effect of different

superdisintegrants like Crospovidone (CP), Croscarmellose sodium (CCS), Sodium

starch glycolate (SSG) on disintegration and dissolution properties of the drug. The

developed formulation tested for all the pharmacoepial and non-pharmacoepial

evaluation as orally dispersible tablets.

The optimized formulation also subjected for the stability study as per ICH

guidelines and in vivo drug release study.

30

Drug Profile 70, 71, 72

Tramadol HCl (USP)

Structure of Tramadol

IUPAC NAME : 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)

cyclohexan-1-ol

Molecular formula : C16H25NO2

Molecular weight : 263.3752 g/mol

Melting point : 180.181 °C

Solubilit : soluble in water

pKa : 9.41

Indications : Indicated in moderate to severe pain in conditions such as

* Arthritis, osteoarthritis and rheumatoid arthritis

* Diabetic neuropathy, trigeminal neuralgia, postoperative neuralgia

* Pain in fractures, disc prolapse, burn, sciatica, dental pains

* Cancer pain

Dose: 50-100 mg every 4 to 6 hours to a maximum dose of 400 mg/day.

31

Mechanism of Action

Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-

receptor agonists. Opiate receptors are coupled with G-protein receptors and

function as both positive and negative regulators of synaptic transmission via

G-proteins that activate effector proteins. As the effector system is adenylate cyclase

and cAMP located at the inner surface of the plasma membrane, opioids decrease

intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of

nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine

and noradrenaline is inhibited. The analgesic properties of Tramadol can be

attributed to norepinephrine and serotonin reuptake blockade in the CNS, which

inhibits pain transmission in the spinal cord. The (+) enantiomer has higher affinity

for the OP3 receptor and preferentially inhibits serotonin uptake and enhances

serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake

by stimulating alpha (2)-adrenergic receptors.

Absorption

Racemic tramadol is rapidly and almost completely absorbed after oral

administration. The mean absolute bioavailability of a 100 mg oral dose is

approximately 75%.The mean peak plasma concentration of racemic tramadol and

M1 occurs at two and three hours, respectively, after administration in healthy

adults.

Toxicity : LD50=350mg/kg (orally in mice)

Protein binding : 20%

Half life : 4to 6hrs

Metabolism

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme

CYP2D6, being O- and N-demethylated to five different metabolites. Of these,M1

(O-Desmethyltramadol) is the most significant since it has 200 times the -affinity

32

of (+)-tramadol, and furthermore has an elimination half-life of nine hours,

compared with six hours for tramadol itself. In the 6% of the population who have

slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II

hepatic metabolism renders the metabolites water-soluble and they are excreted by

the kidneys. Thus reduced doses may be used in renal and hepatic impairment.

Adverse Effects

The most commonly reported adverse drug reactions are nausea, vomiting,

sweating and constipation. Drowsiness is reported, although it is less of an issue

than for other opioids. Respiratory depression, a common side effect of most

opioids, is not clinically significant in normal doses. Tramadol can decrease the

seizure threshold. When combined with SSRIs, tricyclic antidepressents,or in

patients with epilepsy, the seizure threshold is further decreased. Seizures have been

reported in humans receiving excessive single oral doses (700 mg) or large

intravenous doses (300 mg).

-Cyclodextrin 73

Synonyms : Beta-cyclodextrin, ßCD, BCD, ß-Schardinger dextrin,

cyclodextrin B, INS No. 459

Definition : A non-reducing cyclic saccharide consisting of seven

alpha-1, 4-linked Dglucopyranosyl units manufactured by

the action of cyclodextrin transglycolase on hydrolysed

starch followed by purification of the ß-cyclodextrin;

purification is by preparation of a ß-cyclodextrin/solvent

inclusion compound followed by steam-stripping of the

solvent before final purification.

Chemical names : Cycloheptaamylose

Chemical formula : (C6H10O5)7

33

Structural Formula

Formula weight : 1135.00

Description : Virtually odourless, slightly sweet tasting white or

almost white crystalline solid

Functional uses : Encapsulation agent for food additives, flavouring and

vitamins

Solubility : Sparingly soluble in water; freely soluble in hot water;

slightly soluble in ethanol.

34

Excipient Profile

Crospovidone 74

Non proprietary Names

BP : Crospovidone

PhEur : Crospovidonum

USPNF : Crospovidone

Synonyms : Crosspovidonum ; crospopharm ; croslinked

povidone; polyplasdone XL ; polyvinyl

polypyrrolidine.

Chemical name : 1 – ethenyl – 2 - pyrrolidine homopolymer.

Chemical Structure

Description

Crospovidone is a white to creamy-white, finely divided, free flowing,

practically tasteless, odourless or nearly odourless, hygroscopic powder.

Empirical Formula and Molecular Weight

(C6H9NO) n, > 1000000

USP32-NF27 describes crospovidone as a water-insoluble synthetic

crosslinked homopolymer of N-vinyl-2-pyrrolidinone.

35

Applications in Pharmaceutical Formulation

Crospovidone is a water-insoluble tablet disintegrant and dissolution agent

used at 2-5% concentration in tablets prepared by direct compression or wet and

dry-granulation methods. It is rapidly exhibits high capillary activity and

pronounced hydration capacity, with little tendency to form gels. Larger particles

provide a faster disintegration than smaller particles. Crospovidone can also be used

as a solubility enhancer. With the technique of co-evaporation, crospovidone can be

used to enhance the solubility of poorly soluble drugs.

Typical Properties

PH : 5.0 – 8.0

Density : 1.22 g/cm3

Moisture Content : Maximum moisture sorption is approximately 60%.

Solubility : Practically insoluble in water and most common

organic solvents.

Incompatibilities

Crospovidone is compatible with most organic and inorganic pharmaceutical

ingredients. When exposed to a high water level, crospovidone may form molecular

adduct with some materials like sulfathiazole, sodium salicylate, salicylic acid,

Phenobarbital and tannin.

36

Croscarmellose sodium75

Non Proprietary Name

USPNF: Croscarmellose sodium.

Synonyms

Ac-Di-sol; cross-linked corboxy methylcellulose sodium; Primellose.

Structural Formula

Functional category : Tablet and capsule disintegrant.

Chemical name : Cellulose, carboxymethyl ether, sodium salt,

cross-linked.

Description : Croscarmellose sodium occurs as an

odourless, white-coloured powder.

Molecular weight : 90000-700000.

PH : 5.0-7.0.

37

Solubility : Insoluble in water. Although croscarmelose sodium rapidly swells

to 4-8 times of its original volume on contact with water.

Stability and Storage Condition

Croscarmellose sodium is stable though it is hygroscopic material.

A model tablet formulation prepared by direct compression, with Croscarmellose

sodium as disintegrant, showed no significant difference in drug dissolution after

storage at 300C for 14 months.

Incompatibilities

The efficacy of disintegrants, such as Croscarmellose sodium, may be

slightly reduced in tablet formulations prepared by wet granulation or direct

compression process which contain which contain hygroscopic material such as

sorbitol.

Safety

Croscarmellose is mainly used as a disintegrant in oral pharmaceutical

formulations and is generally regarded as an essentially nontoxic and nonirritant

material. However, oral consumption of large amount of Croscarmellose sodium

may have a laxative effect although the quantities used in solid dosage formulations

are unlikely to cause such problems.

Applications : Disintegrant in capsule – 10-25%

Disintegrant in tablets – 0.5-5%

38

Sodium Starch Glycolate 76

Non proprietary Name

BP : Sodium starch glycolate

USPNF : Sodium starch glycolate.

Synonyms : Explotab, Primogel.

Structural Formula

Functional category : Tablet and capsule disintegrant.

Chemical names : Sodium carboxymethyl starch.

Description

Sodium starch glycolate is a white to off-white, odourless, tasteless, free

flowing powder. It consists of oval or spherical granules, 30-100 m in diameter

with some less spherical granules ranging from 10-35 m in diameter.

Solubility : Practically insoluble in water; sparingly soluble in ethanol

(95%). In water it swells upto 300 times its volume.

Stability and

Storage Conditions : It is a stable material. It should be stored in a well closed

container to protect from wide variations in humidity and

temperature that may cause cracking.

39

Incompatibilities : Incompatible with ascorbic acid.

Safety : It is generally regarded as non-toxic and non-irritant

material. However, oral ingestion of large quantities may be

harmful.

Applications : As a disintegrant in tablet (wet granulation and direct

compression) and capsule formulation in 2-8% concentration.

Micro Crystalline Cellulose77

Non Proprietary Names

BP : Microcrystalline Cellulose

JP : Microcrystalline Cellulose

PhEur : Cellulose, Microcrystalline

USP-NF : Microcrystalline Cellulose

Synonyms : Avicel PH; Celex; Cellulose gel; hellulosum

microcristallinum; Celphere; Ceolus KG; crystalline

cellulose; E460; Emcocel; ethispheres .

Structural Formula

40

Description : Microcrystalline cellulose is a purified partially

depolymerised cellulose that occurs as a white, odourless,

tasteless, crystalline powder composed of porous particles. It

is commercially available in different particle sizes and

moisture grades that have different properties and

applications.

Chemical Name : cellulose

Empirical Formula and Molecular Weight

(C6H10O5) n 36000

where n=220

Functional Category : Adsorbent; suspending agent; tablet and capsule

diluents; tablet disintegrant.

Stability and Storage Conditions

Microcrystalline cellulose is a stable through hygroscopic material. The

bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities : Microcrystalline cellulose is a incompatible with strong

oxidizing agents.

Applications

Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a

binder/diluents in oral tablet and capsule formulations where it is used in both wet-

granulation and direct-compression processes. In addition to its use as a

binder/diluents, microcrystalline cellulose also has some lubricant and disintegrant

properties that make it useful in tableting.

41

Colloidal Silicone Dioxide (Aerosil) 78

Nonproprietary Names

BP : Colloidal anhydrous silica

PhEur : Silica colloidalis anhydrica

USPNF : Colloidal silicon dioxide

Synonyms : colloidal silica, fumed silica, light anhydrous

silicic acid, silicic anhydride and silicon

dioxide fumed

Chemical Name : Silica

Molecular Weight : 60.08

Structural Formula : SiO2

Functional Category : Adsorbent, anticaking agent, emulsion

stabilizer, glident, suspending agent, tablet

disintegrant, thermal stabilizer, and viscosity-

increasing agent.

Applications in Pharmaceutical Formulation or Technology

Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and

food products. Its small particle size and large specific surface area gives desirable

flow characteristics that are exploited to improve the flow properties of dry powders

in a number of processes such as tabletting.

Description

Colloidal silicon dioxide is submicroscopic fumed silica with a particle size

of about 15 nm. It is a light, loose, bluish-white-colored, odorless, tasteless, and

non-gritty amorphous powder.

42

Stability and Storage Conditions

Colloidal silicon dioxide is hygroscopic but adsorbs large quantities of

water without liquefying. When used in aqueous systems at a pH 0–7.5, colloidal

silicon dioxide is effective in increasing the viscosity of a system. However, at a pH

greater than 7.5 the viscosity-increasing properties of colloidal silicon dioxide are

reduced; and at a pH greater than 10.7 this ability is lost entirely since the silicon

dioxide dissolves to form silicates. Colloidal silicon dioxide powder should be

stored in a well-closed container. Some grades of colloidal silicon dioxide have

hydrophobic surface treatments that greatly minimize their hygroscopicity.

Aspartame 79

Non proprietary Names

BP : Aspartame

PhEur : Aspartame

USP-NF : Aspartame

Synonyms : aspartamum; aspartyl-L-phenylalaninate.

Chemical Name : N-L- -Aspartyl-L- phenylalanine 1-methyl ester

Structural Formula

43

Empirical Formula and Molecular Weight

C14H18N2O5 294.30

Description : Aspartame occurs as an off white, almost

odourless crystalline powder with an intensely

sweet taste.

Functional Category : Sweetening agent.

Applications in Pharmaceutical Technology

Aspartame is used as an intense sweetening agent in beverage products,

food products, and table-top sweeteners, in pharmaceutical preparations including

tablets, powder mixes, and vitamin preparations. It enhances flavour systems and

can be used to mask some unpleasant taste characteristics; the approximate

sweetening power is 180-200 times that of sucrose.

44

Plan of the Work

Characterization of API

To perform Pre-formulation studies

To develop and optimize the formula for Tramadol Hydrochloride

ODT

Evaluation of Tramadol HCl ODT

* Thickness

* Hardness

* Friability test

* Disintegration time test

* Dispersion time test

* Drug content uniformity

* Dissolution study

* Assay

* Accelerated stability testing

* Invivo studies

45

6.1 Materials

Table 3 List of Materials used in the Study

Sl. No Materials Manufacturer/Suppliers

1 Tramadol HCl KAPL, Banglore

2 cyclodextrinRoquette pharma,

Germany

3 Microcrystalline cellulose KAPL, Banglore

4 Crospovidone KAPL, Banglore

5 Croscarmellose sodium KAPL, Banglore

6 Sodium starch glycolate KAPL, Banglore

7 Aspartame KAPL, Banglore

8 Aerosol KAPL, Banglore

9 Magnesium stearate KAPL, Banglore

10 Talc KAPL, Banglore

11 Mint flavour KAPL, Banglore

46

Table 4 List of equipments

Sl. No Materials Manufacturer/Supplier

1 Electronic weighing balance Mettler Toledo (Germany)

2 Compression Machine Smart press SRC12i (Germany)

3 Hardness and Thickness testerINWEKA Hardness tester

(Germany)

4 Friabilator Electrolab, EF-1W (USA)

5 Dissolution Apparatus USP – Type II Electrolab ED-2 Type-II (USA)

6 FTIR Shimadzu FTIR-8400S (Japan)

7 Hot Air OvenNEWTRONIC HTA

instrumentation (p) LTD (India)

8 UV Spectrometer Shimadzu UV-1601pc (Japan)

47

6.2 Methods

6.2.1 Pharmaceutical Buffer solutions

6.2.1.1 0.1M Hydrochloric Acid (USP) 80

50 ml potassium chloride in a 200 ml volumetric flask, add 85 ml of 0.2M

Hydrochloric acid and then add water to volume.

6.2.1.2 Phosphate Buffer 81

Place 50ml of 1M KH2PO4 in a 200 ml volumetric flask and mix 3.6 ml of

0.2M NAOH and dilute to volume with water.and pH was adjusted to 3.5 with

ortho-phosphoric acid.

6.2.2 Pre-formulation Studies

It is one of the important prerequisite in development of any drug delivery

system. A pre-formulation study concentrates on those physicochemical properties

of the new compound that could affect drug performance and development of

efficacious dosage form. It is the first step in the rational development of the drug

formulation.

6.2.2.1 Melting Point

Melting point of Tramadol HCl was determined by capillary method. Fine

powder of Tramadol HCl was filled in glass capillary tube (previously sealed on one

end). The temperature at which the drug started melting was noted and recorded.

6.2.2.2 Assay

Weigh 50mg of tramadol hydrochloride and transferred to a 100ml

volumetric flask; the volume was made-up with 0.1 N HCl and sonicated for 30 min

to break the complex. The samples were filtered through Whattman filter paper No.

41, diluted suitably and absorbance was measured at 272 nm.

48

6.2.2.3 Preparation of Standard calibration curve of Tramadol Hydrochloride

I Stock solution: A weighed amount of the Tramadol hydrochloride (100mg) was

taken and dissolved in 50ml of 0.1N hydrochloric acid and the volume was made up

with 100ml of 0.1 HCl.

II Stock solution: From the I-stock solution 10ml was withdrawn and diluted to

50ml with 0.1N HCl to get a concentration of 200µg/ml. From standard stock

solution-2 aliquots sample of 1ml, 2ml, 3ml, 4ml, 5ml and 6ml were pipetted into

10ml volumetric flasks. The volume was made up with 0.1 N HCl to get the final

concentration of 20,40,60,80 and 100µg/ml respectively. The absorbance of each

concentration was measured at 272 nm. From standard stock solution-2 aliquots

sample of 1ml, 2ml, 3ml, 4ml, 5ml and 6ml were pipetted into 10ml volumetric

flasks. The volume was made up with 0.1 N HCl to get the final concentration of

20,40,60,80 and 100µg/ml respectively. The absorbance of each concentration was

measured at 272 nm.

6.2.2.4 Compatibility Studies by FTIR

Compatibility with polymers was confirmed by carrying out I R studies.

The pure drug and its formulations along with excipients were subjected to IR

studies. In the present study, the potassium bromide disc (pellet) method was

employed.

6.2.3 Taste Masking

6.2.3.1 Inclusion Complex using -cyclodextrin by Kneading Technique 82, 83

A mixture of Tramadol HCl and cyclodextrin was ground in a glass

container and a minimum amount of water was added Add small quantity and

triturated for 15-30min to get the slurry and air dried at 400c for 24hrs, pulvirised

and passed through sieve no:100 and stored in a dessicator over fused cacl2.

49

6.2.3.2 Estimation of Drug Content of Complex

An accurately weighed amount of Drug-inclusion complex (~100) was

transferred to a 50ml volumetric flask; the volume was made-up with 0.1 N HCl and

sonicated for 30 min to break the complex. The samples were filtered through

Whattman filter paper No. 41, diluted suitably and absorbance was measured at 272

nm.

6.2.4 Preparation of Tablets

Step 1: Sifting of the drug and the excipients

Composition of tablets is mentioned in Table 5. All materials were passed

through sieve no. 40.

Step 2: Disintegrant was divided into two equal parts by weight. Drug complex,

one part of Superdisintegrant and aspartame.

Step 3: Mixing

The sifted step 1 materials were blended for 10mins.

Step 4: Sifting

Blended mass were sifted through 20/40 mesh screen. Ten percent of the

fines were added to the mass and then blended for 2 minutes.

Step 5: Blending and Lubrication

A weighted quantity of Aerosil and remaining superdisintegrant were added

to the mass and blended for five minutes.

Step 6: Compression

The granules of the drug were compressed in a 16 station rotary

compression machine using flat faced punches of 10mm diameter.

50

Table 5 Composition of Oral Dispersible tablet of Tramadol HCl (All

quantities in mg)

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Drug complex 151.2 151.2 151.2 151.2 151.2 151.2 151.2 151.2 151.2

Micro crystallinecellulose

116.3 110.3 104.3 116.3 110.3 104.3 116.3 110.3 104.3

Crospovidone 12 18 24 _ _ _ _ _ _

Croscarmellose _ _ _ 12 18 24 _ _ _

Sodium starchglycolate

_ _ _ _ _ _ 12 18 24

Aspartame 6 6 6 6 6 6 6 6 6

Aerosil 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5

Talc 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5

Magnesiumstearate

2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Mint flavour 3 3 3 3 3 3 3 3 3

Total weight ofthe tablet

300 300 300 300 300 300 300 300 300

51

6.2.5 Evaluation of Granules

6.2.5.1 Bulk Density (Db) 84, 85

It is a ratio of mass of powder to bulk volume. The bulk density depends on

particle size distribution, shape and cohesiveness of particles. Accurately weighed

quantity of powder was carefully poured in to graduate measuring cylinder through

large funnel and volume was measured, which is called initial bulk volume. It is

expressed in gm/ml and is given by

Db = M / V0

where, M is the mass of powder.

V0 is the bulk volume of the powder.

6.2.5.2 Tapped Density (Dt) 86

Ten gram of powder was introduced into a clean, dry 100 ml measuring

cylinder. The cylinder was then tapped 100 times from a constant height and the

tapped volume was read. It is expressed in gm/ml and is given by,

Dt = M / Vt

where, M is the mass of powder.

Vt is the tapped volume of the powder.

6.2.5.3 Flow Properties

Angle of repose, compressibility index and Hausner ratio were evaluated as

per methods described in USP 30-NF25.

6.2.5.3.1 Angle of Repose 86, 87

For determining angle of repose a funnel was mounted on a stand at a fixed

height and a fix weighed quantity of each blend was poured through the funnel. The

52

height and the base diameter of the pile was noted and angle of repose was

calculated as

Angle of repose = tan-1 (height/ 0.5 base)

Table 6 Flow Properties Corresponding to Angle of Repose

Flow character Angle of repose (degrees)

Excellent 25-30

Good 31-35

Fair-aid not needed 36-40

Passable-may hang up 41-45

Poor 46-55

Very poor 56-65

Very, very poor >66

6.2.5.3.2 Compressibility Index and Hausner’s Ratio84

In the recent years compressibility index and the closely related Hausner

ratio have become the simple, fast and popular methods of predicting powder flow

characteristics. The basic procedure to calculate the compressibility index and

Hausner ratio involves measuring the bulk volume (V0) and final tapped volume

(Vf). A 250 ml volumetric cylinder with 100 gm of the material is used for this

purpose. The calculations are done as:

Compressibility index = 100 (Vf- V0 )/ Vf

Hausner ratio = (Vf )/ V0

53

Table 7 Flow Properties Corresponding to Compressibility Index and Hausner

Ratio

Flow character Compressibility index (%) Hausner ratio

Excellent <10 1.00-1.11

Good 11-15 1.12-1.18

Fair 16-20 1.19-1.25

Passable 21-25 1.26-1.34

Poor 26-31 1.35-1.45

Very poor 32-37 1.46-1.59

Very, very poor >38 >1.60

6.2.6 Evaluation of Oral Dispersible Tablets

6.2.6.1 General Appearance and Organoleptic Properties

The control of a general appearance of a tablet involves the measurement of

a number of attributes such as a tablet’s size, shape, color, presence or absence of an

odor, taste, surface texture, physical flaws and consistency, and legibility of any

identifying markings.

6.2.6.2 Shape, Thickness and Dimension85

Six tablets from each batch were selected and measured for thickness and

diameter using digital vernier calipers. The extent to which the thickness of each

tablet deviated from ± 5% of the standard value was determined.

54

6.2.6.3 Hardness

Five tablets from each batch were selected and hardness was measured

using Monsanto hardness tester to find the average tablet hardness.

6.2.6.4 Friability (%F) 85

20 tablets from each batch were selected randomly and weighed. These

tablets were subjected to friability testing using Roche friabilator for 100

revolutions. Tablets were removed, de-dusted and weighed again. Following

formula was used to calculate the % friability

%F =1-(loss in weight/ initial weight) 100

6.2.6.5 Weight Variation88

Weight variation was calculated as per method descried in Indian

Pharmacopoeia (I.P. 1996). 20 tablets were weighed individually and the average

weight was calculated. The requirements are met if the weights of not more than 2

tablets differ by more than the percentage listed in Table and no tablets differ in

weight by more than double that percentage.

Table 8 Weight Variations Allowed as per I.P. 1996

Average weight of tablet (mg) Percentage difference allowed

80 mg or less 10

More than 80 mg but less that 250 mg 7.5

250 mg or more 5

55

6.2.6.6 Drug Content

Finely powder not fewer than 20 tablets. Transfer a portion of the powder,

equivalent to 50mg of tramadol hydrochloride, and transferred to a 100ml

volumetric flask; the volume was made-up with 0.1 N HCl and sonicated for 30 min

to break the complex. The samples were filtered through Whattman filter

paper No. 41, diluted suitably and absorbance was measured at 272 nm.

6.2.6.7 Disintegration Time88

The in-vitro disintegration time was determined by using disintegration test

apparatus. One tablet was placed in each of the six tubes of the apparatus and one

disc was added to each tube. The time in seconds taken for complete disintegration

of the tablet with no palpable mass in the apparatus was measured in seconds.

6.2.6.8 Wetting Time

A Petri dish containing 6 ml of distilled water was used. A tissue paper

folded twice was kept in the dish and a tablet was placed on it. A small quantity of

amaranth red color was put on the upper surface of the tablet. Time required for the

upper surface of the tablet to become red was noted as the wetting time of the tablet.

6.2.6.9 Dissolution Studies

The In vitro dissolution test was carried out using USP Type II dissolution

test apparatus at 37±2°C and 50 rpm speed. 900 ml of 0.1 N HCl was used as

dissolution medium. Aliquot equal to 10 ml was withdrawn at specific time intervals

and amount of Tramadol released from tablet was determined.

6.2.7 Release Kinetics

The results of In-vitro release profile obtained for all the formulations were

plotted in modes of data treatment as follows.

56

1. Log cumulative percent drug remaining versus time (first order

kinetic model)

2. Cumulative percent drug release versus square root of time (Higuchis

model)

3. Cumulative percent drug release versus time (zero order kinetic

model)

4. Log cumulative Percent Drug released versus log time

(korsmeyers model)

6.2.7.1 Drug Release Kinetics-model Fitting of the Dissolution Data 89 -91

Whenever a new solid dosage form is developed or produces, it is

necessary to ensure that drug dissolution occurs in an appropriate manner. Drug

dissolution from solid dosage forms has been described by kinetic models in which

the dissolved amount of drug (Q) is a function of the test time, t or Q = f (t). Some

analytical definitions of the Q (t) function are commonly used such as zero order,

first order, Higuchi, korsmeyers-peppas models. Other release parameters, such as

dissolution time (tx%), dissolution efficacy (ED), difference factor (f1), similarity

factor (f2) can be used to characterize drug dissolution / release profile.

1. Zero-order Kinetics

A zero-order release would be predicted by the following equation.

At = Ao - Kot (1)

where,

At = Drug release at time t

Ao = Initial drug concentration

Ko = Zero-order rate constant (hr)

57

When the data is plotted as cumulative percent drug release versus time if

the plot is linear then the data obeys zero-order release kinetics, with a slope equal to

ko.

Use: This relation can be used to describe the drug dissolution of several types

of modified release pharmaceutical dosage forms, as in case of some

transdermal systems etc. the pharmaceutical dosage forms following this

profile release the same amount of drug by unit of time and it is the ideal

method of drug release in order to achieve a prolonged pharmacological

action.

2. First-order Kinetics

A first order release would be predicted by the following equation.

Log C = Log Co - Kt / 2.303 (2)

where

C = Amount of drug remained at time t

Co = Initial amount of drug

K = First-order rate constant

When the data is plotted as log cumulative percent drug remaining versus

time yields a straight line indicating the release follows first-order kinetics, the

constant k can be obtained by multiplying 2.303 with slope values

Use: The pharmaceutical dosage forms containing water-soluble drugs in porous

matrices, follows this type of dissolution profile. The release of the drug is

proportional to the amount of drug remaining in its interior so that the

amount of drug release by unit of time diminishes

58

3. Higuchi Model

Drug release from the matrix devices by diffusion has been described by

following higuchis classical diffusion equation.

Q = [DE/ (2A- ECs) Cst ] (3)

where

Q = Amount of drug release at time t

D = Diffusion coefficient of the drug in the matrix

A = Total amount of drug in unit volume of matrix

Cs = The solubility of the drug in the matrix

E = Porosity of the matrix

T = Time in hrs at which q is the amount of drug is release

Equation-3 may be simplified if one assumes that D, Cs and A are

constant. Then equation-3 becomes

Q = K t ½

When the data is plotted according to equation-4 i.e. cumulative drug

release versus Square root of time yields a straight line, indicating that the drug was

released by diffusion mechanism. The slope is equal to k.

Use: The relation can be used to describe the drug dissolution from several types

of modified release pharmaceutical dosage forms, as in case of some water

soluble drugs.

4. Korse Meyer Peppas Model

In order to understand the mode of release of drug from swellable matrices,

the data were fitted to the following equation

59

Mt / M = Ktn

where,

Mt / M = the fraction of drug released at time‘t’

K = Constant incorporating the structural and geometrical

Characteristics of the drug / polymer system.

n = Diffusion exponent related to the mechanism of release.

The above equation can be simplified by applying log on both sides we get

Log Mt / M = Log K+ n Log t

When the data is plotted as a log of drug released versus log time, yields a

straight line with a slope equal to n and the k can be obtained from y- intercept.

The value of n for a cylinder is <0.45 for fickian release, > 0.45 and < 0.89

for non-fickian release, 0.89 for the case 2 release and > 0.89 for super case2 type

release.

6.2.8 Stability Studies

The purpose of stability testing is to provide evidence on how the quality of

a drug substance or drug product varies with time under the influence of a variety of

environmental factors such as temperature, humidity and light, and enables

recommended storage conditions and shelf lives to be established.

In the present study, the stability studies were carried out as per ICH

guidelines 400C ± 20C / 75% ± 5% RH for the following selected formulation for 1

month.

Formulation F3

60

After specified time intervals, parameters like physical appearance,

disintegration time, drug content, and dissolution were evaluated according to the

procedure described as earlier.

6.2.9 In vivo Studies 92, 93

Animals: Healthy adult rabbits. (Approval number: IAEC/XXXIV/05/CLB

MCP/2011 dated 07.12.2011)

Procedure: Physical examinations and plasma biochemical analyses were

performed to ensure rabbits were healthy prior to the experiment.

One blood sample was collected before treatment with tramadol

through marginal ear vein. Then, tramadol was administered once,

and blood samples were collected at various time points up to 6hrs

after administration. Blood samples were analyzed with high-

performance liquid chromatography to determine plasma

concentrations of tramadol.

Preparation of mobile phase, stock solution and plasma extraction method

for HPLC analysis:

The mobile phase comprises of phosphate buffer (potassium dihydrogen

phosphate 50mM) and its pH was adjusted to 3.5 using ortho-phosphoric acid. Then

methanol and acetonitrile were added to the buffer solution containing 0.1% triethly

amine. The mobile phase was sonicated and filtered through vacuum filter assembly

by using cellulose acetate filter (0.45_m). A stock solution was prepared by

dissolving 100mg of Tramadol hydrochloride in 100mLof methanol. Working

solutions were prepared in methanol by appropriate dilutions of stock solution. All

the solutions were stored at 200c and protected from light.

To 0.5mL of plasma, 500 ng of Tramadol hydrochloride (dissolved in

0.5mL distilled water) was added and vortexed for 2min. Methanol (2 mL) was

added to the plasma to precipitate plasma proteins and again vortexed for 1 min. The

final solution was subjected to centrifugation at 45,000rpm for 10 min. The

61

supernatant liquid was filtered and transferred to epindroff tube for injecting in

HPLC port. Chromatographic separation was performed at ambient temperature on

ODS hypersil C18 stainless steel analytical column, 5 m pore size, 4.6mm×250mm

and Guard Column.

62

Results

Table 9 Raw Material Analysis of Tramadol Hydrochloride

S. No Test Observation

1 Melting point 1830C

2 Solubility Water, Methanol

3 Assay 99.72%

Determination of Drug Content

When Drug complex was prepared using all of the optimized parameters

for drug loading, the percent drug loading was found to be 99.20% and hence the

drug content was 49.60% w/w.

63

Fig. 4 FTIR Spectrum of Tramadol HCl

Fig. 5 FTIR Spectrum of -cyclodextrin

64

Fig. 6 FTIR Spectrum of Drug Complex

Fig. 7 FTIR Spectrum of Drug Complex with MCC

65

Fig. 8 FTIR Spectrum of Drug Complex with Crospovidone

Fig. 9 FTIR Spectrum of Drug Complex with Cros Carmellose Sodium

66

Fig. 10 FTIR Spectrum of Drug Complex with SSG

Fig. 11 FTIR Spectrum of Drug Complex with Aerosil

67

Fig. 12 FTIR Spectrum of Drug Complex with Magnesium Stearate

Fig.13 FTIR Spectrum of Drug Complex with Aspartame

68

Fig.14 FTIR Spectrum of Drug Complex with Talc

Fig.15 FTIR Spectrum of Drug Complex with flavour

69

Table 10 Standard calibration curve of Tramadol Hydrochloride using pH 1.2

Buffer (0.1M HCl)

S.NoConcentration

(µg/ml)

Absorbance

(nm)

1 0 0.000

2 20 0.126

3 40 0.262

4 60 0.366

5 80 0.484

6 100 0.611

Fig. 16 Standard Calibration Curve of Tramadol Hydrochloride using pH 1.2

Buffer (0.1M HCl)

70

Table 11 Evaluation of precompressed granules of Tramadol HCl

Formulation

Bulkdensity(gm/cc)

±SD

Tappeddensity

(gm/cc) ±SD

Compressibilityindex (%) ±SD

Hausner’sratio

(%)±SD

Angle ofrepose( )

±SD

F1 0.289±0.023 0.344±0.03 13.47±0.002 1.155±0.04 21.98±0.03

F2 0.309±0.021 0.348±0.012 11.02±0.03 1.126±0.01 20.43±0.04

F3 0.296±0.012 0.321±0.02 7.78±0.001 1.084±0.03 19.69±0.02

F4 0.293±0.023 0.316±0.023 7.27±0.012 1.078±0.01 20.79±0.05

F5 0.312±0.032 0.375±0.012 16.80±0.023 1.201±0.02 22.31±0.04

F6 0.295±0.014 0.342±0.021 13.74±0.023 1.159±0.31 21.01±0.21

F7 0.307±0.032 0.370±0.021 17.02±0.001 1.205±0.01 22.24±0.04

F8 0.281±0.041 0.324±0.012 13.27±0.001 1.153±0.02 19.76±0.03

F9 0.318±.021 0.347±0.024 8.35±0.002 1.091±0.03 21.47±0.05

71

Table 12 Evaluation of Compressed Granules of Tramadol Hydrochloride

Formulation Weight Variation Hardness(kg/cm2)

Thickness (mm) Friability(%)

F1 299±0.14 3.48±0.12 3.62± 0.016 0.462

F2 305±0.25 5.65±0.11 3.14±0.012 0.501

F3 301±0.01 4.53±0.14 3.42±0.01 0.442

F4 305±0.43 3.51±0.12 4.14±0.14 0.364

F5 304±0.38 4.21±0.14 3.27±0.03 0.409

F6 302±0.24 4.04±0.15 4.01±0.02 0.486

F7 298±0.18 4.79±0.14 3.93±0.12 0.423

F8 304±0.16 4.23±0.16 3.76±0.01 0.412

F9 306±0.41 4.54±0.13 4.15±0.13 0.389

72

Table 13 Evaluation of Compressed Granules of Tramadol Hydrochloride

Formulation Wetting Time (sec)Disintegrating

Time (sec)Drug content

(%)

F1 75 31 98.23

F2 41 24 98.76

F3 23 18 99.12

F4 29 20 101.76

F5 30 27 100.14

F6 35 29 98.99

F7 29 32 99.01

F8 31 27 98.66

F9 27 26 98.41

73

Table 14 Invitro Dissolution Profile of Tramadol HCl from ODTs (F1)

S.No Time (min) cumulative % drugrelease ± SD

1 5 63.87±0.48

2 10 71.12±0.32

3 15 82.93±0.56

4 20 91.47±0.21

5 30 98.88±0.18

All values are expressed as mean ± SD, n=3

Fig. 17 Invitro Dissolution Profile of Tramadol HCl from ODTs (F1)

74

Table 15 Invitro Dissolution Profile of Tramadol HCl from ODTs (F2)

S.No Time (min) cumulative % drugrelease ± SD

1 5 67.31±0.42

2 10 74.02±0.12

3 15 82.35±0.41

4 20 90.20±0.23

5 30 97.15±0.32

All values are expressed as mean ± SD, n=3

Fig. 18 Invitro Dissolution Profile of Tramadol HCl from ODTs (F2)

75

Table 16 Invitro Dissolution Profile of Tramadol HCl from ODTs (F3)

S.No Time (min) cumulative % drugrelease ± SD

1 5 61.05±0.16

2 10 69.66±0.12

3 15 78.11±0.32

4 20 90.29±0.21

5 30 99.18±0.18

All values are expressed as mean ± SD, n=3

Fig. 19 Invitro dissolution profile of Tramadol HCl from ODTs (F3)

76

Table 17 Invitro dissolution profile of Tramadol HCl from ODTs (F4)

S.No Time (min)cumulative % drug

release ± SD

1 5 65.81±0.32

2 10 74.42±0.12

3 15 82.32±0.16

4 20 89.38±0.21

5 30 94.87±0.18

All values are expressed as mean ± SD, n=3

Fig. 20 Invitro Dissolution Profile of Tramadol HCl from ODTs (F4)

77

Table 18 Invitro Dissolution Profile of Tramadol HCl from ODTs (F5)

S.No Time (min)cumulative % drug

release ± SD

1 5 59.11±0.21

2 10 67.15±0.16

3 15 76.10±0.23

4 20 87.21±0.12

5 30 96.74±0.34

All values are expressed as mean ± SD, n=3

Fig. 21 Invitro Dissolution Profile of Tramadol HCl from ODTs (F5)

78

Table 19 Invitro Dissolution Profile of Tramadol HCl from ODTs (F6)

S.No Time (min)cumulative % drug

release ± SD

1 5 67.89±0.16

2 10 74.92±0.32

3 15 85.83±0.21

4 20 90.58±0.23

5 30 97.54±0.14

All values are expressed as mean ± SD, n=3

Fig. 22 Invitro Dissolution Profile of Tramadol HCl from ODTs (F6)

79

Table 20 Invitro Dissolution Profile of Tramadol HCl from ODTs (F7)

S.No Time (min)cumulative % drug

release ± SD

1 5 68.71±0.16

2 10 75.45±0.25

3 15 81.06±0.13

4 20 92.84±0.21

5 30 98.42±0.33

All values are expressed as mean ± SD, n=3

Fig. 23 Invitro Dissolution Profile of Tramadol HCl from ODTs (F7)

80

Table 21 Invitro Dissolution Profile of Tramadol HCl from ODTs (F8)

S.No Time (min)cumulative % drug

release ± SD

1 5 72.49±0.23

2 10 81.62±0.21

3 15 88.51±0.33

4 20 94.96±0.14

5 30 97.21±0.17

All values are expressed as mean ± SD, n=3

Fig. 24 Invitro Dissolution Profile of Tramadol HCl from ODTs (F8)

81

Table 22 Invitro Dissolution Profile of Tramadol HCl from ODTs (F9)

S.No Time (min) cumulative % drugrelease ± SD

1 5 69.11±0.42

2 10 77.83±0.32

3 15 84.83±0.21

4 20 91.59±0.17

5 30 97.86±0.25

All values are expressed as mean ± SD, n=3

Fig. 25 Invitro Dissolution Profile of Tramadol HCl from ODTs (F9)

82

Determination of Release Kinetics:

Table 23 Kinetic Studies of Oral Dispersible Tablets

Release kinetics R2 Intercept SlopeZero order 0.971 54.48 1.573

First order 0.908 2.142 0.067

Higuchi 0.982 32.33 12.31

Korsmeyer peppas 0.972 1.577 0.280

Dissolution- Zero Order Kinetics

Fig. 26 Graph for the Formulation F3-Zero Order Kinetics

83

Dissolution- First Order Kinetics

Fig. 27 Graph for the Formulation F3-First Order Kinetics

84

Fig. 28 Graph for the Formulation F3-Higuchi model

Fig. 29 Graph for the Formulation F3- Korse Meyer Peppas model

85

Stability Studies

Table 24 Stability Studies for F3 Formulation of Tramadol Hydrochloride

ODT at 40º C /75 % RH

Batch number andstability condition Assay (%) Dissolution study in pH

1.2 buffer40º C/75 % RH

( Initial )99.12% 99.18±0.16%

40º C/75 % RH

( 15 days )99.64% 99.14±0.32%

40º C/75 % RH

( 1 month )99.64% 99.76±0.12%

All values are expressed as mean ± SD, n=3

Table 25 Stability Studies for F3 Formulation of Tramadol Hydrochloride

ODT at 40º C /75 % RH

Batch numberand stability

conditionFriability (%) Hardness

( kg/cm2 )Disintegration

time (sec)

40º C/75 % RH

( Initial )0.442 4.53±0.14 18

40º C/75 % RH

( 15 days )0.482 4.49±0.10 18

40º C/75 % RH

( 1 month )0.469 4.55±0.12 19

86

Fig. 30 in vivo Calibration Curve in Plasma

87

Table 26 invivo Pharmacokinetic Parameters for Marketed Formulation

Time (hr) Area (%) Concentration (ng/ml)

0 0 0

1 95.36 122.13

2 355.67 414.58

4 86.45 112.72

6 26.45 44.71

Fig. 31 invivo Pharmacokinetic Parameters for Marketed Formulation

88

Table 27 Pharmacokinetic Parameters of Marketed Product

Cmax 414.6

Tmax 2.0

AUC( 0-t) 1014.2 ng-hr/ml

AUC( ) 1110.8 ng-hr/ml

AUMC ) 3325.1 ng-hr*hr/ml

E Phase 716.463

D/A Phase 830.576

MRT (area) 3.0 hr

89

Table: 28 invivo Pharmacokinetic Parameters for Tramadol Hydrochloride (F3)

Time (hr) Area (%) Concentration (ng/ml)

0 0 0

1 81.42 98.42

2 289.58 371.51

4 61.35 85.83

6 19.16 30.16

Fig: 32 invivo pharmacokinetic parameters for Tramadol hydrochloride (F3)

90

Table 29 Pharamacokinetic parameters of Tramadol hydrochloride (F3)

Cmax 371.5

Tmax 2.0

AUC( 0-t) 857.5 ng-hr/ml

AUC( ) 915.2 ng-hr/ml

AUMC ) 2536.8 ng-hr*hr/ml

E Phase 695.112

D/A Phase 772.892

MRT (area) 2.8 hr

91

7. Discussion

7.1 Raw Material Analysis of Tramadol Hydrochloride

The experimental work started with raw material analysis of Tramadol

hydrochloride. Parameters of Tramadol HCl given in the I.P were in compliance and

reported in the Table 9.

7.2 Compatibility Study with Excipients

Fig 4 shows the FTIR spectra of plain Tramadol Hydrochloride

IR spectra of pure Tramadol HCL showed bands at 3000 for aliphatic C-H

stretch, 2930 for CH2 absorptions, for isopropyl group shows bands near 1170 and

1145.

IR spectra of drug and excipients physical mixture shown in Fig 5-15 also

revealed that no considerable change was observed in bands of Tramadol HCl;

hence it indicates the absence of interaction between the drug and excipients used in

the tablet.

7.3 Standard Calibration Curve for Tramadol Hydrochloride

The calibration curve of Tramadol hydrochloride in 0.1M HCl was derived

from the concentration and corresponding absorbance values. Linear regression

analysis gave the equation for the line of best fit as Y=0.006X+0.005. Linearity was

observed in the concentration range between 20 to 100 g/ml. The values were

shown in Table 10 and Fig 16.

7.4 Formulation Development

Tramadol hydrochloride is opoid analgesic; attempts have been made to

develop the oral dispersible tablets. The superdisintegrants used were Crospovidone,

Croscarmellose sodium and SSG used as disintegrating agents which decreases the

92

disintegrating time and the effect of superdisintegrants on the drug release was

studied.

7.5 Preparation of Oral Dispersible Tablets

Tramadol Oral Dispersible Tablets were prepared using different

percentages of Crospovidone, Croscarmellose sodium and SSG as superdisintegrants

by direct-compression method.

The granules prepared using Crosspovidone for compression of orally

disintegrating tablets was evaluated. Angle of repose was in the range of 19.69±0.02

to 21.98±0.03. Bulk density & Tapped density has 0.289±0.023 to 0.309±0.0210 &

321±0.012 to 0.348±0.02. Compressibility index & Hausner’s ratio was found to

have in limit of 7.78±0.001 to 13.47±0.002 & 1.084±0.032 to 1.155±0.04. These

values indicate that the prepared granules exhibited good flow properties. The

results were shown in Table 11.

The granules prepared by using Crospovidone were compressed to tablets

and tablets are tested for its physical characteristics. The thickness of the tablets was

in the range of 3.14±0.012 to 3.62±0.016. The friability has 0.442 to 0.501. The

hardness & weight variation is in between 3.48±0.12 to 5.65±0.11 & 299±0.14 to

305±0.25. The wetting time & Disintegration time showed the values in the range of

23 to 75 & 18 to 31. The drug content varied in between 98.23 to 99.12. The results

are shown in Table 12-13.

The granules prepared using Crosscarmellose sodium for compression of

orally disintegrating tablets was evaluated. Angle of repose was in the range of

20.79±0.05 to 22.31±0.001. Bulk density & Tapped density was found to have in the

range of 0.293±0.023 to 0.312±0.032 & 0.316±0.023 to 0.375±0.012.

Compressibility index & Hausner’s ratio lie in between 7.27±0.012 to 13.74±0.023

& 1.078±0.012 to 1.159±0.0041. These values indicate that the prepared granules

exhibited good flow properties. The results were shown in

Table 11.

93

The granules prepared by using Croscarmellose sodium were compressed

to tablets and tablets are tested for its physical characteristics. The thickness of the

tablets was in between 3.27±0.03 to 4.14±0.14. The friability & hardness of the

tablets was 0.364 to 0.486 & 3.51±0.12 to 4.53±0.14. The weight variation of the

tablets lies in the range 302±0.24 to 305±0.43. The wetting time of the tablets was in

the range of 29 to 35. Disintegrating time of the tablets was in the range of 20 to 29.

The drug content varied in between 98.99 to 101.76. The results are shown in Table

12-13.

The granules prepared using Sodium starch glycolate for compression of

orally disintegrating tablets were evaluated. Angle of repose was in the range of

19.76±0.03 to 22.24±0.04. Bulk density & Tapped density was in the between

0.281±0.041 to 0.318±.021 & 0.324±0.012 to 0.370±0.021. Compressibility index

was in range of 8.35±0.002 to 17.02±0.001. Hausner’s ratio was in the range of

1.091±0.031 to 1.205±0.012. These values indicate that the prepared granules

exhibited good flow properties. The results were shown in

Table 11.

The granules prepared by using Sodium starch glycolate were compressed

to tablets and tablets are tested for its physical characteristics. The thickness of the

tablets was in the range of 3.76±0.01 to 4.15±0.13. The friability of the tablets was

found to be in between 0.389 to 0.423. The hardness of the tablets was in the limit of

4.23±0.16 to 4.79±0.14. The weight variation of the tablets was in the range of

298±0.18 to 306±0.41. The wetting time & Disintegrating time lies in between 27 to

31 & 26 to 32. The drug content varied in between 98.41 to 101.76. The results are

shown in Table 12-13.

7.6 Invitro Dissolution Studies

On immersion in 0.1M HCl, pH 1.2 solution at 37±0.50 c all oral

dispersible tablets remained buoyant up to 30 min.

94

7.6.1 Effect of Crospovidone on Drug Release

F1, F2, F3 were prepared by using Crospovidone as superdisintegrant and

the drug release for these formulation was given in the Table 14-16, Fig 17-19. The

release of drug for F1 at 5th & 30th minute was found to be 63.87% & 98.88%. The

release of drug for F2 at 5th minute was 67.31% and at 30th minute 97.15%. The

release of drug for F3 at 5th & 30th minute shows 61.05% & 99.18%

Crosspovidone due to their non-ionic nature, pyrolidone chemistry and

porous particle morphology, will rapidly absorb water via capillary action. During

tablet compaction, the highly compressible crospovidone particles become highly

deformed. The deformed particles come in contact with water that is wicked into the

tablet resulting in rapid volume expansion and hydrostatic pressure that cause tablet

disintegration. Due its high crosslink density, crospovidone swells rapidly in water

without gelling.

Other super disintegrants, like sodium starch glycolate and croscarmallose

sodium have lower crosslink density and as a result, form gels when fully hydrated,

particularly at higher use.

7.6.2 Effect of Croscarmellose Sodium on Drug Release

F4, F5, F6 were prepared by using Croscarmellose sodium as

superdisintegrant and the drug release for these formulation was given in the

Table 17-19, Fig 20-22. The release of drug for F4 at 5th minute was 65.81% and at

30th minute 94.87%. The release of drug for F5 at 5th shows 59.11% and at 30th

minute was found to be 96.74%. The release of drug for F6 at 5th minute & 30th

minute was 67.89% & 97.54%.

Croscarmellose sodium is an internally cross-linked sodium

carboxymethylcellulose for use as a disintegrant in pharmaceutical formulations.

The cross-linking reduces water solubility while still allowing the material to swell

and absorb many times its weight in water. As a result, it provides superior drug

95

dissolution and disintegration characteristics, thus improving formulas subsequent

bioavailability.

7.6.3 Effect of Sodium Starch Glycolate on Drug Release

F7, F8, F9 were prepared by using Sodium starch glycolate as

superdisintegrant and the drug release for these formulation was given in the

Table 20-22, Fig 23-25. The release of drug for F7 at 5th minute was found to be

68.71% and at 30th minute shows 98.42%. The release of drug for F8 at 5th minute

was found to be 72.49% and at 30th minute was found to be 97.21%. The release of

drug for F9 at 5th minute & 30th minute has 69.11% & 97.86%.

Sodium starch glycolate generally elastic in nature that they deform under

pressure. But, with the compression forces involved in tabletting will deform it more

to swell it higher. As a result it provides the dissolution.

7.7 Stability Study

Stability studies were conducted for the formulation F3. The stability study

was performed at 400 C±20 C/75% RH for a specific period of time. The tablets were

analysed for Disintegration time, Friability, Drug content, Hardness and In vitro

dissolution studies. The overall results showed that the formulation is stable at the

above mentioned storage conditions shown in Table 24-25.

7.8 In vivo Studies

In vivo studies were done to find out the pharmacokinetic parameters of the

optimized formulation with the market product.

The Cmax for the innovator product was found to be 414.58ng/ml and for

the Tramaol hydrochloride (F3) was found to be 371.51ng/ml. The concentration of

the innovator product and Tramadol hydrochloride (F3) in plasma has nearly same.

96

The Tmax of the innovator product and Tramadol hydrochloride (F3) shows

at 2nd hour. AUC(0-t) for the innovator product and Tramadol HCl (F3) was 1014.2

ng-hr/ml & 8575.5 ng-hr/ml. AUMC ) shows 332.1 ng-hr*hr/ml & 2536.8 ng-

hr*hr/ml for innovator product and Tramadol HCl.

97

Summary

Chapter 1(P-1) begins with a general introduction presenting an overview

of oral dispersible tablets, in the part of the introduction the advantages,

disadvantages of oral dispersible tablets were discussed thoroughly. Introduction

shows the topic selected was worth investigating in the field of search.

Chapter 2(P-19) described the literature review carried out for selected

drug, superdisintegrants and design and evaluation of oral diapersible tablets.

Chapter 3(P-29) detailed the aim and objective of the present study.

Chapter 4(P-30) detailed the information of the selected drug, and also

excipients used in formulating oral dispersible tablets.

Chapter 5(44) described the plan of work.

Chapter 6(45) deals with the methodology followed for the preparation of

oral dispersible tablet after raw material analysis and drug excipient compatibility

studies. The detailed procedure for the preparation and evaluation of oral dispersible

tablet was mentioned.

Chapter 7(62) shows the results and detailed discussion of all the

formulations all the quantitative and qualitative parameters were analyzed. The raw

material analysis was carried out as per I.P and which met with specifications of I.P.

The Drug-Excipient compatibility study was done and found to have no interaction.

The physical charactersistics was done for all the formulations and the

results were found to be satisfactory. Invitro dissolution studies were done for

Tramadol HCL oral disintegrating tablet prepared with different concentrations of

Crospovidone, Croscarmellose sodium and SSG were compared and discussed.

Formulation F3 was found to have less disintegration time and maximum drug

release with in 30 mins.

98

Stability studies were carried out for F3 by keeping the tablets at 400 C ± 20

C, 75% ± 5% RH for specific period of time. The physical parameters and drug

release of F3 were not altered much on storage conditions for specific period of time

which shows that the optimized formulation is found to be stable.

Invivo studies were done to find out the pharmacokinetic parameters of the

optimized formulation with the marketed product.

99

Conclusion

The formulation containing 50mg of Tramadol hydrochloride was prepared

as orally dispersible tablet. These techniques are particularly useful for geriatrics and

pediatrics can be taken without the aid of water.

The optimized formulation have consistent release profile to provide the

disintegration with in one minute by Crospovidone (F3).The short term stability

study also indicates no change in the physical characteristic of drug content.

The comparision of pharmacokinetic parameters between the ODTs

Tramadol HCl and conventional tablet, showed no major changes in the

pharmacokinetic parameters. Hence, it can be concluded that the ODTs of Tramadol

HCl was successfully developed and evaluated.

100

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